p38 Mitogen-Activated Protein Kinase- and HuR-Dependent Stabilization of p21Cip1 mRNA Mediates the G1/S Checkpoint
p38 Mitogen-Activated Protein Kinase- and HuR-Dependent Stabilization of p21Cip1 mRNA Mediates the G1/S Checkpoint
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DOI：
10.1128/mcb.00210-09
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发表时间：
2009-08-15
影响因子：
5.3
通讯作者：
Nebreda, Angel R.
中科院分区：
文献类型：
--
作者：
Lafarga, Vanesa;Cuadrado, Ana;Nebreda, Angel R.
p38丝裂原活化蛋白激酶（mitogen-activated protein kinase，MAPK）的激活在DNA损伤诱导的G（2）/M期细胞阻滞中起重要作用，但该信号通路在G（1）/S转换中的作用尚不清楚。细胞周期蛋白依赖性激酶抑制剂p21（Cip 1）的上调被认为是γ射线诱导的G（1）/S细胞周期阻滞的主要原因。我们在这里表明，p38 MAPK的抑制会损害p21（Cip 1）的积累，从而损害细胞响应γ辐射而停滞在G（1）的能力。我们发现，p38 MAPK诱导p21（Cip 1）mRNA的稳定，而不影响其转录或蛋白质的稳定性。特别是，p38 MAPK磷酸化Thr 118上的mRNA结合蛋白HuR，这导致HuR的细胞质积累及其与p21（Cip 1）mRNA的结合增强。我们的研究结果有助于理解p38 MAPK在细胞对DNA损伤的反应中的新作用，并揭示存在p53非依赖性网络，该网络在G（1）/S检查点协同调节p21（Cip 1）水平。
Activation of p38 mitogen-activated protein kinase (MAPK) plays an important role in the G(2)/M cell cycle arrest induced by DNA damage, but little is known about the role of this signaling pathway in the G(1)/S transition. Upregulation of the cyclin-dependent kinase inhibitor p21(Cip1) is thought to make a major contribution to the G(1)/S cell cycle arrest induced by gamma radiation. We show here that inhibition of p38 MAPK impairs p21(Cip1) accumulation and, as a result, the ability of cells to arrest in G(1) in response to gamma radiation. We found that p38 MAPK induces p21(Cip1) mRNA stabilization, without affecting its transcription or the stability of the protein. In particular, p38 MAPK phosphorylates the mRNA binding protein HuR on Thr118, which results in cytoplasmic accumulation of HuR and its enhanced binding to the p21(Cip1) mRNA. Our findings help to understand the emerging role of p38 MAPK in the cellular responses to DNA damage and reveal the existence of p53-independent networks that cooperate in modulating p21(Cip1) levels at the G(1)/S checkpoint.